tbuckley/cabot-search huggingface dataset:
Differences in treatment outcomes in relation to level of human epidermal growth factor receptor-2 (HER2) expression, HER2-low vs HER2-zero, in patients with hormone receptor-positive metastatic breast cancer treated with cyclin dependent kinase CDK4/6 inhibitors: A systematic review and meta-analysis.
Authors: Baha' Sharaf, Abdulrahman Ahmad Alhajahjeh, Lana I Batarseh, Hala Abu-Fares, Hikmat Abdel-Razeq
Journal: Journal of Clinical Oncology (2023)

e13081 Background: Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancers (MBC) are usually treated with endocrine therapy (ET) in combination with cyclin dependent kinase (CDK4/6) inhibitors. Such combinations have significantly improved treatment outcomes. HER2-negative MBC have recently been divided into two subgroups: HER2-zero, with an immunohistochemistry (IHC) score of 0, and HER2-low, with an IHC score of 1+ or 2+ and a negative in situ hybridization (ISH) assay. The aim of this meta-analysis is to compare treatment outcomes of these two groups of MBC patients when treated with a combination of ET and CDK4/6 inhibitors. Methods: A systematic literature review was conducted to identify relevant studies on the level of HER2 expression in breast cancer patients treated with CDK4/6 inhibitors. The review included articles in databases such as Medline via PubMed, Embase, and Cochran Library, as well as abstracts from the ASCO meeting and SABCS conference updated tell January 2023. Eligible studies included randomized controlled trials, prospective or retrospective studies, and case-control studies that compared the difference in PFS between HER2-low and HER2-zero among breast cancer patients treated with CDK4/6 inhibitors in first-line or beyond setting. A meta-analysis was performed to determine the pooled hazard ratio for progression-free survival (PFS). In addition, a pooled survival curve was created by digitizing the Kaplan-Meier curves to create pseudo-individual patients’ data following the methodology outlined by Combescure et. al (2014). Results: In total, 7 different studies were identified that included a total of 1,341 patients. The random effect model shows a statically significant shorter PFS in the HER2-low group; 17.2 months compared to 24.0 months in HER2-zero group (HR=1.55; 95% CI [1.27-1.84]; p &lt;0.001). There was no statically significant heterogeneity between the studies (I 2 =51% p-value=0.07). The PFS rates at 12, 24, 36, and 48 months for HER2-low were as follow: (66.2%; 95% CI [50.0%-87.5%]), (33.2 %; 95% CI= 17.4%-63.4%), (26.2%; 95% CI= 12.8%-53.38%), and (22.05%; CI95%= 10.32%-47.12%), respectively compared to: (77.73%; 95% CI= 64.45%-93.75%), (50.00%; 95% CI= 34.66%-72.13%),(43.58%; 95% CI= 22.91%-82.89%), and (36.85%; 95% CI= 17.60%-77.15%) among patients with HER2-zero. Conclusions: In patients with MBC treated with CDK4/6 inhibitors, level of HER2 negativity may affect treatment outcomes; patients with HER2-zero had better PFS compared to those with HER2-low disease. Such findings, if confirmed in larger studies, may change the landscape of treatment of this group of patients.
Deep learning-based ensemble model using hematoxylin and eosin (H&amp;E) whole slide images (WSIs) for the prediction of MET mutations in non-small cell lung cancer (NSCLC).
Authors: Yoon-La Choi, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Taebum Lee, Seunghwan Shin, Jongchan Park, Minuk Ma, Sergio Pereira, Gahee Park, Seulki Kim, Juneyoung Ro, Wonkyung Jung, Donggeun Yoo, Chan-Young Ock
Journal: Journal of Clinical Oncology (2023)

e13578 Background: The MET proto-oncogene is involved in tumorigenesis and progression and has emerged as an attractive targetable genomic alteration in NSCLC. However, it has not been actively tested in NSCLC due to the lack of a cost-effective screening tool. We developed a deep-learning based model to predict genomic profiles from H&amp;E WSI and applied it to MET pathologic mutations in NSCLC. The prediction model is based on an ensemble model trained not solely on H&amp;E images but also on multi-layered semantic contents that were produced by a pre-trained AI analyzer, Lunit SCOPE IO. Methods: The model was trained on the MET aberration (exon 14 skipping, n=191; pathogenic mutation, n=109) and paired wild-type dataset (n=500). To extract deep features from raw H&amp;E images, a self-supervised vision transformer was used, and an AI-based pathology profiling analyzer extracted semantic contents such as the spatial information of tumor cells, lymphocytes, cancer epithelium, and cancer stroma. A set of classifiers was trained based on the two features, and the ensemble of these features was used to improve robustness. Following cross-validation, the model was applied to an independent clinical dataset with MET sequencing results from The Cancer Genome Atlas (TCGA) LUAD and LUSC datasets (n=914), Samsung Medical Center (SMC, n=361), and Chonnam National University Hospital (CNUH, n=54). Results: The best cross-validation performances of the models predicting MET aberration measured by mean area under the receiver operating characteristic curve (AUROC) were 0.772 when trained by only H&amp;E images (HE-only), 0.788 by AI semantic content with MLP classifier (AISC-MLP), and 0.803 by AISC with random forest (AI-RF), respectively. An ensemble of the three models showed an increased AUROC of 0.837 in the training dataset by cross-validation. These models were applied to the external validation dataset (n=1,329), including 20 (1.5%) MET exon 14 skipping and known pathologic mutations. The mean AUROC to predict MET aberration by the ensemble model was 0.817 with 95% sensitivity, 64.7% specificity. The AUROC of TCGA, SMC, and CNUH cohorts were 0.815, 0.802, and 0.812, respectively. Conclusions: An AI-based ensemble model combining H&amp;E images with semantic contents extracted from pre-developed AI models significantly improved the accuracy and robustness of MET pathogenic mutation prediction using an H&amp;E sample in NSCLC. These findings allow for cost-effective screening for MET alterations.
Association of anthracyclines induced cardiotoxicity (AIC) in patients with early breast cancer (eBC) with germline BRCA1/2 (gBRCA1/2) mutation: BRCAN study.
Authors: Juan José Serrano Domingo, David Cordero, Miriam Menacho, Jose Manuel del Rey, Jesús Chamorro, Diana I. Rosero, Pilar Sotoca, Laura del Campo, Gonzalo Alonso, Cristina Saavedra Serrano, María Fernández-Abad, Maria Gion Cortes, Eva M. Guerra, Noelia Martinez-Jañez, Elena Lopez-Miranda, Elena Maria Vida Navas, Raquel Fuentes Mateos, CARMEN GUILLEN PONCE, Maria Teresa Salazar, Alfonso Cortés Salgado
Journal: Journal of Clinical Oncology (2023)

567 Background: BRCA1/2 genes play a critical role in genome stability and DNA repair in human cells, including cardiomyocytes. In animal models, loss of cardiomyocyte-specific BRCA1/2 is associated with DNA damage, apoptosis, cardiac dysfunction, and cardiac mortality following anthracyclines (A) exposure. However, whether these preclinical findings translate to humans still remains unclear. We conducted the BRCAN study to assess the impact of gBRCA1/2 status on AIC in a cohort of patients with eBC. Methods: This is a single center retrospective/prospective study including patients diagnosed with HER2-negative eBC treated with A based chemotherapy in the neo/adjuvant setting, known gBRCA1/2 status, left ventricular ejection fraction (LVEF) ≥ 50% at baseline and no previous significant cardiovascular events. During follow-up, we performed myocardial dysfunction blood biomarkers (MDBB), cardiac ultrasound and quality of life questionnaires (QoL). Primary objective was to assess the absolute LVEF change from baseline in BRCA1/2 mutation carriers (gBRCA1/2mut) versus non-carriers (gBRCA1/2wt). Secondary objectives were comparing MDBB and QoL in these groups. Results: 137 patients with eBC were included in the study (103 gBRCA1/2wt and 34 gBRCA1/2mut). Patients’ characteristics were similar between both groups in terms of age, baseline LVEF, radiotherapy (RT) on left side, total A accumulative dose, time from A exposure, antihypertensive or hypolipidemic agents use and smoking habit. Compared to baseline, LVEF % reduction was -4.7 [-12.0, 0.0] versus -9.5 [-18.0, -5.0] in gBRCA1/2wt and gBRCA1/2mut, respectively (p=0.027). To correct for confounding, we fit a regression model for the variables smoking habit, antihypertensive and hypolipidemic agents use. On average, LVEF % reduction in gBRCA1/2mut group was -4.5 [CI 95% -8.6, -0.4, p=0.032] compared to gBRCA1/2wt. No differences between MDBB (protein C-reactive, hsTn, NT-ProBNP, D-Dimer, ST-2 or Galectine-3) and QoL (MLHFQ and EQ5-D index) were detected between groups. Conclusions: Our data suggest that gBRCA1/2mut patients could represent a high risk population for AIC. A baseline comprehensive cardiovascular risk assessment and a closer follow-up should be recommended in these patients. Further research is needed on order to identify early predictive biomarkers for AIC. [Table: see text]
Tumor-infiltrating lymphocytes (TILs) for prediction of response to platinum-based neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC).
Authors: Sheyda Abdullaeva, Tatiana Semiglazova, Anna Artemyeva, Vladislav Semiglazov, Petr Krivorotko, Vladimir Semiglazov
Journal: Journal of Clinical Oncology (2023)

e12620 Background: According to several previous trials the rate of pathological complete response (pCR) for patients with TNBC is increased when carboplatin is added to NACT. However, it is largely unknown which group of patients would truly benefit from platinum-based NACT and for whom chemotherapy could be de-escalated. Several clinical trials have evaluated the stromal TILs as an important prognostic and predictive biomarker in breast cancer. We assessed the pCR rates and the outcomes in patients with TNBC randomized to receive NACT ± Carboplatin regarding TILs status. Methods: The clinical data were obtained from 132 patients diagnosed with TNBC (ER&amp;PgR &lt; 10%) and treated with either anthracycline-taxane NACT (n = 68) or сarboplatin-based chemotherapy (n = 64) from 2017 to 2022 at N.N. Petrov National Medicine Research Center of Oncology. TILs were evaluated in 132 formalin-fixed paraffin-embedded tumor tissue samples stained with H&amp;E at baseline biopsies according to guidelines from the International TILs Working Group. Classification of TILs into low ( &lt; 10%), intermediate (≤10% to &lt; 40%) and high (≥ 40%) levels was performed. Data are presented using the methods of descriptive statistics. The differences between groups were assessed using the Сhi-square test. P-values below 0.05 were considered statistically significant. Results: The proportion of patients who achieved a pCR was higher in the carboplatin group 66% than in patients without carboplatin 35% (OR 3,5; 95% CI 1,71-7,17; p = 0,0006). There were 25 (18.9%), 77 (58.3%) and 30 (22.7%) patients with low ( &lt; 10%), intermediate (≤10% to &lt; 40%) and high (≥ 40%) levels of TILs, respectively. In total, the tumors with high TILs had a pCR rate of 63.3%, compared with 46.1% for low TILs (OR 2,0; 95% CI 0,87-4,67; p = 0,097). No significant statistical difference in pCR rates was shown between carboplatin-based and standard NACT groups with high TILs - 71% and 54%, respectively (OR 2,06; 95% CI 0,45-9,30; p = 0,346). When analyzing a group with low TILs infiltration, the pCR was more frequent in the platinum-based 64% compared to 31% in the standard NACT group (OR 3,9; 95% CI 1,72-9,00; p = 0,0011). Conclusions: These data may support the de-escalation of carboplatin-based NACT in patients diagnosed with TNBC with high TILs infiltration. Further investigations are warranted to explore the predictive value of TILs in platinum-based NACT. [Table: see text]
Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neoadjuvant and postoperative adjuvant anti-HER2 therapy: Flamingo-01.
Authors: Snehal Patel, Jaye Thompson, Mira Patel, F. Joseph Daugherty, Mothaffar F. Rimawi
Journal: Journal of Clinical Oncology (2023)

TPS617 Background: GP2 is a biologic nine amino acid peptide of the HER2/ neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient was treated with GLSI-100, survived, and was followed for more than 6 months ( p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events observed were considered related to the immunotherapy. Methods: This Phase III trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. The patient population is defined by these key eligibility criteria: HER2/neu positive and HLA-A*02; residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy; exclude stage IV; completed at least 90% of planned trastuzumab-based therapy. Trial objectives were to determine if GP2 therapy increases IBCFS, to assess the safety profile of GP2 and to monitor immunologic responses to treatment and assess relationship to efficacy and safety. The study has been initiated at a number of sites in the US. The study is also expected to be opened in Spain, Germany, and France. Clinical trial information: NCT05232916 .
Evolution of breast cancer management in the Dominican Republic in the 21<sup>st</sup> century.
Authors: Robens Molaire, Miguel Monanci, Dayanara Hidalgo
Journal: Journal of Clinical Oncology (2023)

e12500 Background: Breast cancer is a major public health problem. Despite knowing the management, clinicians are forced to provide less than optimal care when diagnostic and/or treatment are lacking. For that, we decided to do a review about breast cancer treatment during the 21 st century in Dr. Heriberto Pieter Oncology Institute. Methods: A retrospective study was done to describe and evaluate the management of patients with breast cancer. A random sample of 100.00 patients was selected, which was reduced to 64.00 after the inclusion-exclusion criteria application like lacking immunohistochemistry, partial treatment. and less than 5 years with the diagnosis. Results: Molecular subtypes included luminal A: estrogen receptor + and/or progesterone receptor + , Her2Neu 3 - (44%); luminal B: estrogen receptor + and/or progesterone receptor + , Her2Neu 3+ (9%); Her2Neu 3 : estrogen receptor-, progesterone receptor - , Her2Neu 3+ (19%); basal-like: estrogen receptor - , progesterone receptor - , Her2Neu 3- (28%). Chemotherapy history: 63% with neoadjuvant chemotherapy; 78% with adjuvant chemotherapy, 18.75% as primary and 59.37% as secondary; 17% with palliative chemotherapy, 3% as primary and 14% as secondary. Surgical history: 31% with primary modified radical mastectomy (MRM), 63% with secondary MRM, and 2% with quadrantectomy. Radiotherapy: 11% with primary radiation therapy (RT), 36% with secondary RT, and 3% with palliative RT. Hormonal therapy of patients: 33% with tamoxifen, 11% with aromatase inhibitors, 8% with combination of hormonal therapy, and 22% with extended adjuvant hormone therapy of more than 5 years. Primary endpoints were disease-free survival at 5 years (67%), objective response rate to neoadjuvant chemotherapy (100% according to RECIST criteria), and overall survival at 5 years (87.5%). Currently in Dominican Republic there is availability of more target therapy for Her2Neu 3 like pertuzumab, lapatinib, other drugs for positive hormone receptor named CDK4/6 inhibitors (palbociclib, ribociclib), olaparib for germline BRCA mutation and pembrolizumab for basal like or triple negative breast cancer (TNBC). Finally, according to the latest World Health Organization (WHO) data published in 2020, breast cancer deaths in Dominican Republic reached 1,460 or 2.14% of total deaths. The age adjusted death rate is 28.28 per 100,100 and the number of new cases in 2020 for breast cancer was 3,412 (17.2%). Conclusions: This review allows us to track the evolution of breast cancer management in Dominican Republic during the 21 st century. It highlights the efforts made to apply guidelines on breast cancer management in general and global objective response to neoadjuvant regimen. It also highlights the need to implement more primary prevention and early detection since 52% of patients belong to the locally advanced category. [Table: see text]
Real-world treatment patterns in patients with HER2+ unresectable or metastatic breast cancer: Interim results from HER2 REAL Asia cohort.
Authors: Soo-Chin Lee, Wei-Pang Chung, Roger Kai-Cheong Ngan, Seock-Ah Im, Rina Hui, Carlos Barrios, Teresa Tung
Journal: Journal of Clinical Oncology (2023)

1047 Background: HER2 REAL (NCT04857619) is the first multi-country, retrospective study exploring the treatment practices and outcomes in patients (pts) with HER2+ locally advanced, unresectable (u)/metastatic (m) breast cancer (BC) from routine clinical care in the APAC and LATAM. Methods: Adult HER2+ u/mBC pts diagnosed since reimbursement or wider access of trastuzumab emtansine (T-DM1) or 01 Jan 2017, whichever was earlier with ≥12 months (mo) of follow-up data from index date (u/mBC diagnosis) and treated with ≥1-line of therapy (LOT) were enrolled per medical chart review from 6 countries. Here we present interim descriptive analyses (cut-off 30 June 2022) on demographics, clinical characteristics, and treatment patterns. Results: Of the 763 enrolled pts, 370 with median (range) age of 55 (20–81) yrs from Hong Kong, Korea, Singapore, and Taiwan were eligible for interim analyses; 368 (99.5%) were female with 210 (57.1%) postmenopausal. A total of 210 (57.1%) pts with reported data had a median time of 2 (0–18) yrs from initial BC diagnosis to u/mBC relapse. At index date, majority had ductal carcinoma (227/254 [89.4%]), visceral (255/355 [71.8%]), and non-visceral (258/355 [72.3%]) metastases; 80/355 (22.5%) had CNS metastases. Family history of BC was reported by 45/370 (12.2%) pts completing the questionnaire; 209/370 (56.5%) had hormone receptor-positive BC. Treatments reported in the first to fifth line were quite variable. HER2-directed therapy was received by 323/367 (88.0%) in LOT1 (mainly trastuzumab [TRA] and pertuzumab [PTZ]-based) and 298/343 (86.9%) in LOT2 (mainly T-DM1). Median duration of LOT1 and LOT2 were 7.8 (0–130) and 5.0 (0–100) mo, respectively, that decreased to 2.3 (0–30) mo in LOT5. The prime reason for treatment discontinuation was disease progression (LOT1: 294 [80.1%]; LOT2: 273 [79.6%]; LOT3: 187 [68.5%]). Serious adverse effects from treatments were rare (LOT1: 7 [1.9%]; LOT2: 10 [2.9%]; LOT3: 5 [1.8%]). Conclusions: The interim analyses show heterogeneous treatment patterns in real-world among pts with HER2+ u/mBC progressing on HER2-directed therapies possibly due to access disparity in these 4 Asian countries. Clinical trial information: NCT04857619 . [Table: see text]
Real-world (RW) outcomes of patients (pts) with advanced breast cancer (aBC) with and without resistance alterations (alts) detected in cell-free circulating tumor DNA (ctDNA) prior to CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) treatment.
Authors: Seth Andrew Wander, Caroline M. Weipert, Jiemin Liao, Anton Safonov, Nicole Zhang, Aditya Bardia, Pedram Razavi
Journal: Journal of Clinical Oncology (2023)

1081 Background: CDK4/6i plus ET is standard of care first-line (1L) therapy for hormone receptor positive (HR+), HER2- aBC. While molecular analyses from trials and pts have identified several mechanisms of resistance to CDK4/6i plus ET, currently, no biomarkers (outside of hormone status) are used for therapy selection. We utilized RW data to assess impact of putative baseline CDK4/6i+ET resistance alts (CDK4/6i+ET-R) on clinical outcomes among pts with aBC treated with CDK4/6i. Methods: Pts with aBC were identified via the Guardant INFORM database; those with a ctDNA test within 90 days prior to CDK4/6i start were included in this analysis. Based on previous studies, oncogenic or likely oncogenic alterations (as characterized by OncoKB) in the following genes were considered CDK4/6i+ET-R alts: RB1, PTEN, AKT1, CCNE1, ERBB2, FGFR1, FGFR2, and KRAS. Pts with &gt;1 CDK4/6i+ET-R alt were compared to pts without any CDK4/6i-R alts. Kaplan-Meier plots, log-rank tests (LR) and multivariate Cox proportional hazards models (HR) adjusted (adj) for age, sex, year of ctDNA test and line of therapy were used to assess differences in time to next treatment (TTNT) and overall survival (OS). Results: 1075 pts with aBC treated with CDK4/6i (27% receiving 1L treatment) met inclusion criteria, 293 of whom (27%) had &gt;1 alt in a CDK4/6i+ET-R gene. Pts with CDK4/6+ETi-R alts had significantly shorter TTNT (8.7 mos vs 14.2 mos, LR p=0.001; adj HR 1.36, 95%CI 1.11-1.66, adj p=0.003) and OS (28.3 mos vs 60.9 mos, LR p=&lt;0.0001; adj HR 2.19, 95%CI 1.69-2.82, adj p=&lt;0.0001) compared to those without. This divergence was more pronounced for patients receiving 1L CDK4/6i (TTNT: 10.7 mos vs 24.6 mos, LR p=0.006, adj HR 1.84, 95%CI 1.18-2.87, adj p=0.007; OS: 23.8 mos vs 67.3 mos, LR p&lt;0.0001, adj HR 3.27, 95%CI 1.89-5.62, adj p&lt;0.0001). Individual gene contributions towards less favorable TTNT are shown. Conclusions: We demonstrate via RW data that patients with &gt;1 pre-treatment ctDNA alt in a curated list of CDK4/6i+ET-R genes have significantly worse outcomes on CDK4/6i plus ET treatment, a difference more pronounced among patients receiving 1L therapy. This data is among the first successful efforts to validate a clinically useful multi-gene clinical biomarker that has the potential to predict CDK4/6i plus ET resistance. Further exploration of this signature’s prognostic and predictive utility for CDK4/6i plus ET use is ongoing to better refine personalized treatment selection in HR+/HER2- aBC. [Table: see text]